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Abnormal response to methylphenidate across multiple fMRI procedures in cocaine use disorder: feasibility study.

ABSTRACT: The indirect dopamine agonist methylphenidate remediates cognitive deficits in psychopathology, but the individual characteristics that determine its effects on the brain are not known.We aimed to determine whether targeted dopaminergically modulated traits and individual differences could predict neural response to methylphenidate across multiple functional magnetic resonance imaging (fMRI) procedures.We combined neural measures from three separate procedures (two inhibitory control tasks differing in their degree of emotional salience and resting-state functional connectivity) during methylphenidate (20 mg oral, versus randomized and counterbalanced placebo) and correlated these aggregated responses with cocaine use disorder diagnosis (22 cocaine abusers, 21 controls), symptoms of attention deficit hyperactivity disorder, and working memory capacity.Cocaine abusers, relative to controls, had a lower response in the dorsolateral prefrontal cortex to methylphenidate across all three procedures, driven by responses to the two inhibitory control tasks; reduced methylphenidate fMRI response in this region further correlated with more frequent cocaine use.Cocaine abuse (and its frequency), associated with lower tonic dopamine levels, correlated with a reduction in activation to methylphenidate (versus placebo). These initial results provide feasibility to the idea that multimodal fMRI tasks can be meaningfully aggregated, and that these aggregated procedures show a common disruption in addiction in a highly anticipated region relevant to cognitive control. Results also suggest that drug use frequency may represent an important modulatory variable in interpreting the efficacy of pharmacologically enhanced cognitive interventions in addiction.

SUBMITTER: Moeller SJ

PROVIDER: S-EPMC4916842 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Abnormal response to methylphenidate across multiple fMRI procedures in cocaine use disorder: feasibility study.

Moeller Scott J SJ Konova Anna B AB Tomasi Dardo D Parvaz Muhammad A MA Goldstein Rita Z RZ

Psychopharmacology 20160506 13

<h4>Rationale</h4>The indirect dopamine agonist methylphenidate remediates cognitive deficits in psychopathology, but the individual characteristics that determine its effects on the brain are not known.<h4>Objectives</h4>We aimed to determine whether targeted dopaminergically modulated traits and individual differences could predict neural response to methylphenidate across multiple functional magnetic resonance imaging (fMRI) procedures.<h4>Methods</h4>We combined neural measures from three se ...[more]

PMID: 27150080

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Project description:Cocaine use disorder (CUD) is a debilitating condition with no NICE-recommended medication or specific psychosocial interventions. In the United Kingdom (UK), general counselling (treatment-as-usual; TAU) is widely delivered, but has limited effectiveness. We tested the feasibility, safety and preliminary efficacy of a novel, adjunctive psychosocial intervention for CUD, called 'memory-focused cognitive therapy' (MFCT).We did a two-arm, external pilot randomised controlled trial at a specialist community National Health Service addictions clinic in London, UK. 30 adults (?18years), voluntarily seeking treatment for CUD (enrolled ?14days; all with moderate-to-severe DSM5 CUD), were individually randomised (1:1) to a control group (ongoing TAU; 3×90min CUD cognitive conceptualisation assessments; 2×30min cocaine-related cue-induction procedures; and 3×30min research follow-ups); or to an intervention group (ongoing TAU; 3×90min cognitive conceptualisation assessments; 2×30min cocaine-related cue-induction procedures; 5×120min, one-to-one, MFCT sessions [in 1week]; and 3×60min research follow-ups and MFCT-relapse prevention). The primary outcome was the total percentage score on the frequency version of the Craving Experiences Questionnaire (CEQ-F) at 1-month follow-up after the intensive intervention week (clinical endpoint; recall period past 2weeks; higher score indicating greater craving). Secondary outcomes at the 1-month follow-up were percentage days abstinent (PDA) from cocaine, and longest period (days) of continuous abstinence (LPA) in the prior 28days. Outcomes were analysed as an unadjusted group mean difference (with Hedge's g effect size [ES]) and a 95% Confidence Interval [CI] for the primary outcome and a 90% CI for the secondary outcomes. Exploratory, multivariable linear (primary outcome) and Poisson regression models (secondary outcomes), with sex, age, months of regular cocaine use, baseline outcome score, and group estimated the effectiveness of the intervention. The trial is registered with the ISCRTN (ISRCTN16462783).Between July 15, 2015, and November 27, 2016, 58 patients were assessed for eligibility and 30 participants were randomised (14 to the control group and 16 to the intervention). With outcome data collected for all participants at the endpoint, the intervention group mean CEQ-F score (14·77; SD 21·47) was lower than the control group mean (51·75; SD 22·72); ES -1·62; 95% CI -2·45 to -0·80. MFCT was associated with more cocaine abstinence in the intervention group (PDA 85·94; SD 18·96) than the control group (PDA 54·59; SD 30·29); ES 1·19; 90% CI 0·54 to 1·84. There was also greater maximum abstinence in the intervention group (LPA 15·69; SD 10·10) than the control group (6·00; SD 7·36); ES 1·06; 90% CI 0·41 to 1·70. Exploratory, confounder-adjusted regression models for this preliminary effect supported the treatment association for reduced craving experiences (CEQ-F Coef. -28·25; 95% CI -45·15 to -11·35); more abstinence (PDA Incidence Rate Ratio [IRR] 1·56; 95% CI 1·31 to 1·88); and greater maximum abstinence (LPA IRR 2·56; 95% CI 1·96 to 3·35), although relative weak unmeasured confounding could overturn these model-adjusted exposure-outcome associations. There were four serious adverse events (among three participants). None were judged related to study procedures or interventions.In this first external pilot randomised controlled trial of MFCT for CUD, we have shown that the intervention and control procedures and acceptable feasible and safe, and report preliminary evidence that MFCT is associated with reduced craving and increased abstinence. These findings support progression to a substantive trial.UK National Institute for Health Research, Biomedical Research Centre.

Project description:Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and (18)FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2-5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction.

Dataset Information

Abnormal response to methylphenidate across multiple fMRI procedures in cocaine use disorder: feasibility study.

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Abnormal response to methylphenidate across multiple fMRI procedures in cocaine use disorder: feasibility study.

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